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Original Investigation |

Phosphorylated Tau as a Candidate Biomarker for Amyotrophic Lateral Sclerosis

Murray Grossman, MD, EdD1; Lauren Elman, MD1; Leo McCluskey, MD, MSc1; Corey T. McMillan, PhD1; Ashley Boller, BA1; John Powers, BA1; Katya Rascovsky, PhD1; William Hu, MD, PhD2; Les Shaw, PhD3; David J. Irwin, MD1,3; Virginia M.-Y. Lee, MD, MBA3; John Q. Trojanowski, MD, PhD3
[+] Author Affiliations
1Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
2Department of Neurology, Emory University, Atlanta, Georgia
3Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania
JAMA Neurol. 2014;71(4):442-448. doi:10.1001/jamaneurol.2013.6064.
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Importance  An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary.

Objective  To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.

Design, Setting, and Participants  A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center.

Main Outcomes and Measures  The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau).

Results  Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n = 51) and ALS Functional Rating Scale–Revised (n = 42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n = 10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex.

Conclusions and Relevance  The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.

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Figure 1.
Boxplots of Cerebrospinal Fluid (CSF) Analytes Phosphorylated Tau at Threonine 181 (ptau), Total Tau (ttau), and ptau:ttau Ratio in Amyotrophic Lateral Sclerosis (ALS), 4-Repeat Tauopathy (4R-Tau), and Healthy Elderly Participants (Seniors)

Dark lines in boxplots illustrate median CSF value, notches illustrate interquartile range (nonoverlapping notches are significantly different), error bars represent the 25th to 75th percentile range of data, and circles represent outliers.

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Figure 2.
Receiver Operating Characteristic Curve

The sensitivity and specificity of cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (ptau), total tau (ttau), and ptau:ttau ratio in amyotrophic lateral sclerosis relative to 4-repeat tauopathies is shown.

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Figure 3.
Reduced White Matter Fractional Anisotropy (FA) in Amyotrophic Lateral Sclerosis and 4-Repeat Tauopathy (4R-tau), and Regressions Relating Adjusted Cerebrospinal Fluid Phosphorylated Tau at Threonine 181 (ptau) to Total Tau (ttau) Ratio to FA

A, Right anterior view of anatomic distribution of reduced FA in ALS (q < 0.05, false–discovery rate corrected; green). Red areas indicate anatomic distribution of regressions relating adjusted ptau:ttau ratio to FA in corticospinal tract, prefrontal centrum semiovale, and body of corpus callosum (not illustrated). B, Left anterior view of anatomic distribution of reduced FA in 4R-tau (q < 0.005, false–discovery rate corrected; green). Red areas indicate anatomic distribution of regressions relating adjusted ptau:ttau ratio to FA in midbrain, right uncinate (not illustrated).

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